TMPRSS2

Chr 21

transmembrane serine protease 2

Also known as: PRSS10

NCBI Gene: 7113 ENSG00000184012 UniProt: O15393

This protein is a plasma membrane-anchored serine protease that cleaves proteins at arginine residues and participates in proteolytic cascades important for normal prostate function. The gene is extremely tolerant to loss-of-function variants (very low constraint), and no Mendelian diseases have been definitively associated with TMPRSS2 mutations in pediatric populations. While the protein facilitates viral entry including SARS-CoV-2 and influences prostate cancer progression, these are not monogenic pediatric neurogenetic conditions.

Summary from RefSeq, UniProt

P/LP submissions

P/LP missense

0.94

LOEUF

Multiple*

Mechanism· predicted

Clinical Summary— TMPRSS2

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

75 unique Pathogenic / Likely Pathogenic· 23 VUS of 138 total submissions

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Clinical Trials

11 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint

0.94LOEUF

pLI 0.000

Z-score 1.81

OE 0.65 (0.46–0.94)

Tolerant

Typical tolerance to LoF variation

Missense Constraint

0.40Z-score

OE missense 0.94 (0.85–1.03)

303 obs / 323.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.65 (0.46–0.94)

0≤0.351.4

Missense OE0.94 (0.85–1.03)

0≤0.61.4

Synonymous OE0.92

0≤1.21.6

LoF obs/exp: 20 / 30.9Missense obs/exp: 303 / 323.2Syn Z: 0.76

0.75top 25%

GOF

0.7029th %ile

LOF

0.2580th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

138 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic73

Likely Pathogenic2

VUS23

Likely Benign11

Benign11

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	73	0	73
Likely Pathogenic	0	0	2	0	2
VUS	1	16	6	0	23
Likely Benign	0	6	2	3	11
Benign	0	6	0	5	11
Total	1	28	83	8	120

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

TMPRSS2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Conditions Influencing Health StatusHealthyProstate Cancer

Comparing the Reliability of Expressed Prostatic Secretion (EPS) and Post Massage Urine (PMU) for the Prediction of Prostate Cancer Biopsy Outcome

ACTIVE NOT RECRUITING

NCT01441687Phase NACity of Hope Medical CenterStarted 2009-07-14

laboratory biomarker analysistransrectal prostate biopsy

Prostate Cancer

Circulating Tumor Cell Analysis in Patients With Localized Prostate Cancer Undergoing Prostatectomy

RECRUITING

NCT01961713Massachusetts General HospitalStarted 2010-04

Metastatic Hormone Naive Prostate Cancer

In Men With Metastatic Prostate Cancer, What is the Safety and Benefit of Lutetium-177 PSMA Radionuclide Treatment in Addition to Chemotherapy

ACTIVE NOT RECRUITING

NCT04343885Phase PHASE2Peter MacCallum Cancer Centre, AustraliaStarted 2020-04-21

177Lu-PSMA-617Docetaxel

Prostate Cancer

Comparative Study of Radiotherapy Treatments to Treat High Risk Prostate Cancer Patients

ACTIVE NOT RECRUITING

NCT02303327Phase PHASE3Sir Mortimer B. Davis - Jewish General HospitalStarted 2015-01

EBRT + HDR brachytherapy boostHypofractionated Dose Escalation RadiotherapyAndrogen deprivation therapy

Prostate Cancer

The Predictive Value of Coexisting TMPRSS2-ERG Gene Fusion and PTEN Deletion in Prostate Cancer Patients with Biochemical Failure Status Post Salvage or Radical Radiation Therapy

RECRUITING

NCT02573636Sir Mortimer B. Davis - Jewish General HospitalStarted 2016-03

PSAProstate Cancer

EDRN Prostate MRI Biomarker Study

RECRUITING

NCT03784924University of MichiganStarted 2019-02-04

MRI prostate

Prostate CancerMetastatic Castration-resistant Prostate Cancer

ProsTIC Registry of Men Treated With PSMA Theranostics

RECRUITING

NCT04769817Peter MacCallum Cancer Centre, AustraliaStarted 2021-05-01

177Lu-PSMA